Daniel Lee
University of Kentucky, KY·Neuroscience
In Alzheimer's disease and related tauopathies, a protein called tau clumps into toxic tangles inside brain cells. These tangles track closely with memory loss and nerve cell death, and no treatments yet change the course of these diseases.
- Fields
Neuroscience
Biochemistry
Pharmacology
- Topics
Alzheimer's disease
tauopathy
neurodegeneration
- Grants
- 2 known grants, through Jan 2028
What they work on
- Test how the arginine sensor CASTOR1, a brake on the growth regulator mTORC1, improves lysosome function, repair and clearance of protein clumps when cell models are stressed by tau or lysosome-damaging agents.
- Determine how proteotoxic stress disrupts arginine metabolism and buildup using new FRET-based arginine biosensors, fluorescent reporters that report arginine levels inside cells.
- Use CASTOR1 knockout mice to test how losing this arginine sensor affects cognition, tau pathology and the spread of tau between neurons.
- Determine how gain or loss of neuronal PAD4, the enzyme that citrullinates tau, changes tau pathology and behavior, using overexpression and conditional knockout mice in tauopathy models.
- Test how PAD4-driven citrullination of tau alters its clearance, aggregation, seeding and microtubule binding in cell models and biochemical assays, and map citrullinated tau and its seeding activity in human tauopathy brains.
More about the research
One reason the clumps build up is that cells fail to clear damaged proteins. Much of this cleanup normally happens in lysosomes, the cell's recycling compartments. Two projects ask how chemical changes to proteins, centered on the amino acid arginine, affect tau buildup and its removal. One project studies a sensor protein that detects arginine. The other studies an enzyme-driven modification of tau's own arginines.
Why it matters
Alzheimer's disease and other tauopathies currently have no treatments that change their course. By identifying how the arginine sensor CASTOR1 and the citrullinating enzyme PAD4 control tau buildup and clearance, this work could point to new drug targets. It could also open strategies to boost lysosome function and slow neurodegeneration in patients with Alzheimer's disease and related dementias.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Zuoshang Xu
University of Massachusetts Chan Medical School, MA·Neuroscience
Map which spinal cord proteins are citrullinated and how this changes across disease stages, using proteomics in SOD1 G93A and PFN1 C71G ALS mouse models.
Allison L Kraus
Case Western Reserve University, OH·Neuroscience
Define the age of onset, amount, brain location and chemical variety of tau seeds in diseased, normal, young and older human brains, using RT-QuIC seed amplification assays specific to 3R, 4R and 3R/4R tau.
David Eisenberg
University of California-Los Angeles, CA·Biochemistry
Discover safe Tau disaggregants through repeated cycles of solving structures of Alzheimer's brain Tau fibrils bound to compounds and screening new compounds that fit the drug-binding site.
The school
University of Kentucky: 34 labs on PI Pages, $528M a year on research, 319 research doctorates a year.
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